Apolipoprotein E4, Cholinergic Integrity, Synaptic Plasticity and Alzheimer’s Disease

Abstract

Recent evidence indicates that apolipoprotein E (apoE) plays a central role in the hippocampal response to injury. The coordinated expression of apoE and its receptor, the apoE/apoB (LDL) receptor, appears to regulate the transport of cholesterol and phospholipids during the early and intermediate phases of the reinnervation process. During dendritic remodelling and synaptogenesis, neurons progressively repress the synthesis of cholesterol in favor of choles terol internalization through the apoE/LDL receptor pathway. The discovery that the apolipoprotein E4 allele is strongly linked to both sporadic and familial late onset Alzheimer’s disease (AD) raises the possibility that a dysfunction of the lipid transport system associated with compensatory sprouting and synaptic remodelling could be central to the AD process. The role of apoE in the central nervous system is particularly important in relation to the function of the cholinergic system, which relies to a certain extent on the integrity of phospholipid homeostasis in neurons. Recent evidence indicates that the apoE4 allele has a direct impact on cholinergic function and on cholinomimetic drug response in AD subjects.